Variants in the exonuclease domain of the polymerase proofreading genes POLE and POLD1 cause polymerase proofreading-associated polyposis, which is a dominant-inheritance and high-penetrance hereditary syndrome conferring a predisposition to attenuated colorectal polyposis and early-onset CRC (Palles et al., 2013). The gene discussed is POLE; the disease is colorectal carcinoma.